#5: How to Comply with the Pediatric Research Equity Act

On September 7, 2005, FDA announced the availability of a draft guidance, entitled "How to Comply with the Pediatric Research Equity Act," providing sponsors with a number of recommendations regarding how the pediatric study requirements of the Pediatric Research Equity Act (PREA) should be interpreted.

What is PREA?

PREA was enacted by Congress on December 3, 2003. It requires pharmaceutical companies to conduct pediatric studies of certain drugs and biological products. According to the draft guidance, "PREA is the most recent of more than a decade of legislative and regulatory attempts to address the lack of pediatric use information in drug product labeling."

Requirements of PREA

Statutory Requirements

• Unless a waiver or deferral has been obtained, PREA requires applications for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration to contain a pediatric assessment.
• PREA grants FDA with the authority to require application holders of previously approved New Drug Applications (NDAs) or Biologics License Applications (BLAs) to submit a pediatric assessment under certain circumstances.
• PREA applies only to products developed for the treatment of diseases/conditions that occur in both adult and pediatric populations.
  • Products that are intended for pediatric-specific indications are only subject to PREA requirements if initially developed for a subset of the relevant pediatric population.

Scope of Requirements

• PREA does not apply to products that have been granted Orphan Drug Designation (ODD) by the FDA. However, the Agency states that "if only one indication for a product has orphan designation, a pediatric assessment may still be required for any applications to market that same product for the non-orphan indication(s)."
• In general, the requirements under PREA do not apply to Abbreviated New Drug Applications (ANDAs) for generic drugs. However, ANDAs that are submitted under an abbreviated stability petition for changes regarding dosage form, route of administration, or new active ingredients in combination products are subject to PREA's pediatric assessment requirements.

The Pediatric Assessment

The pediatric assessment is made up of data from pediatric studies using appropriate formulations for each age group. This is done in order to:

• Assess the safety and effectiveness of the product in all pediatric subpopulations.
• Support dosing and administration for each pediatric subpopulation for which the product is found to be safe and effective.

Unless a deferral or waiver has been granted, PREA states that the pediatric assessment must be submitted at the time of the application's submission.

Type of Data Included in the Pediatric Assessment

The type of data that must be submitted under PREA is dependent on a number of factors, including:

• Nature of the application
• What is known about the product in pediatric populations
• Underlying disease or condition being treated

According to its draft guidance, FDA states that "applicants should contact the appropriate review division to discuss the types of pediatric studies needed to complete their pediatric assessments."

The Pediatric Plan & Submissions

A pediatric plan does the following:

• Outlines the pediatric studies that the applicant plans to conduct.
• Addresses the development of an age-appropriate formulation.
• Addresses whether and, if so, under what grounds, the applicant plans to request a waiver or deferral.

According to the draft guidance, FDA encourages all applicants to submit their pediatric plans to the Agency as soon as possible in the drug development process. In addition, applicants are also advised to discuss these plans with FDA at critical points in the development process.

For products intended for life-threatening or severely debilitating illnesses, applicants are encouraged to discuss the pediatric plan at the Pre-IND Meeting and End-of- Phase 1 (EOP1) meetings. This will allow the Agency to provide its best judgement on whether the pediatric studies will be required under PREA, and, if so, whether the submission will be deferred until after approval.

For products not intended for life-threatening or severely debilitating illnesses, FDA recommends that applicants submit and discuss the pediatric plan no later than the End-of-Phase 2 (EOP2) meeting. At this point, the review division will provide its best judgement regarding:

1. The pediatric assessment that will be required from the product.
2. Whether its submission can be deferred.
3. If deferred, the date that the studies will be due.

The FDA states that the appropriate age ranges to be studied may vary depending on the product, the manifestation of the disease in various age groups, and the ability to measure the response to therapy. However, in general, the pediatric population includes patients age birth to 16 years of age, including age groups often referred to as neonates, infants, children, and adolescents.

Pediatric Formulations

PREA states that all applicants "must submit requests for approval of the pediatric formulation used in their pediatric studies, and failure to submit such a request may render the product misbranded." According to its draft guidance, FDA interprets ‘request for approval of a pediatric formulation' to mean that an application must be submitted for any formulation used in the conduct of pediatric studies that has not been previously approved. Furthermore, it may also be necessary for applicants to develop the pediatric formulation before the pediatric clinical trial is initiated.

It is possible for FDA to waive the requirement for pediatric studies in certain age groups requiring a pediatric formulation if the applicant is able to demonstrate that it has made reasonable attempts and failed to produce the formulation necessary for that age group. However, this exception is only applicable to the pediatric groups requiring that specific formulation. This partial waiver generally applies only to situations where "unusually difficult technological problems prevented the development of a pediatric formulation."

Information to Submit to FDA

In the draft guidance, FDA states that pediatric studies for drugs that are conducted under an IND are subject to all of the rules governing INDs. These include:

• Content and format requirements
• IND safety reporting requirements
• Annual reporting requirements

In general, when submitted as a part of an application or supplement to an application, the content and format of the study reports must meet the relevant requirements for submission.

Waivers

Based on established criteria, PREA grants FDA with the authority to waive or defer the pediatric assessment requirement for some or all pediatric age groups.

FDA can grant full or partial waivers, and they can be made on the Agency's initiative or at the request of the applicant.

Criteria for Full

According to the draft guidance, a full waiver will be granted if FDA finds one or more of the following:

1. "Necessary studies are impossible or highly impracticable (because, for example, the number of patients is so small or the patients are geographically dispersed) (section 505B(a)(4)(A)(i) of the Act)."
2. "There is evidence strongly suggesting that the drug or biological product would be ineffective or unsafe in all pediatric age groups (section 505B(a)(4)(A)(ii) of the Act)."
3. "The drug or biological product (1) does not represent a meaningful therapeutic benefit over existing therapies for pediatric patients, and (2) is not likely to be used in a substantial number of pediatric patients (section 505B(a)(4)(A)(iii) of the Act)."

Criteria for Partial Waiver

The Agency will grant a partial waiver if the applicant certifies and FDA finds evidence of one or more of the following:

1. "Necessary studies are impossible or highly impracticable (because, for example, the number of patients in that age group is so small or patients in that age group are geographically dispersed) (section 505B(a)(4)(B)(i) of the Act)."
2. "There is evidence strongly suggesting that the drug or biological product would be ineffective or unsafe in that age group (section 505B(a)(4)(B)(ii) of the Act). If a partial waiver is granted based on evidence that the drug is unsafe or ineffective in pediatric populations, the applicant must include this information in the labeling for the drug or biological product (section 505B(a)(4)(D) of the Act)."
3. "There is evidence strongly suggesting that the drug or biological product would be ineffective or unsafe in that age group (section 505B(a)(4)(B)(ii) of the Act). If a partial waiver is granted based on evidence that the drug is unsafe or ineffective in pediatric populations, the applicant must include this information in the labeling for the drug or biological product (section 505B(a)(4)(D) of the Act)."
4. "The applicant can demonstrate that reasonable attempts to produce a pediatric formulation for that age group have failed (section 505B(a)(4)(B)(iv) of the Act). If a waiver is granted on the basis that it is not possible to develop a pediatric formulation, the waiver shall cover only the pediatric groups requiring that formulation (section 505B(a)(4)(C) of the Act)."

Waivers that are agreed to at the EOP2 meeting will be documented in the meeting minutes, stating whether a full or partial waiver has been granted. Decisions to waive the pediatric assessment requirement that are made early can be reconsidered by the Agency at any time. "A waiver decision becomes final once issued in the approval letter for an NDA, BLA, or supplement."

Deferrals

A deferral does not exempt a sponsor from submitting the required pediatric assessment, rather it simply permits the applicant to submit the assessment after the submission of the NDA, BLA, or supplemental NDA/BLA. Like waivers, deferrals can be made on FDA's initiative or at the request of the sponsor.

Applying for a Deferral

The timing for the submission of some or all of the required pediatric studies may be deferred if FDA finds one or more of the following:

1. "The drug or biological product is ready for approval for use in adults before pediatric studies are complete."
2. "Pediatric studies should be delayed until additional safety or effectiveness data have been collected."
3. "There is another appropriate reason for deferral."

In order to obtain a deferral, sponsors must submit certification for the reason(s) for deferring the assessments, a description of the planned or ongoing studies, and evidence that the studies are being conducted or will be conducted with due diligence at the earliest possible time.

Deferral decisions are made on a case-by-case basis, and according to a number of considerations that help FDA determine whether and how long to defer submission of the pediatric assessment.

Compliance with PREA

It is extremely important that sponsors are in compliance with all of PREA's requirements. According to FDA's draft guidance, "if a pediatric assessment or a request for approval of a pediatric formulation is not submitted by an applicant in accordance with the statutory requirements, the drug or biological product may be considered misbranded solely because of that failure and subject to relevant enforcement action."

Navigating the requirements of PREA can be tricky. With so many options and loopholes, it is important to ensure that you are headed in the right direction and on the path to approval. We can help you do this. We have a 33-year track record of helping our clients receive successful interactions with FDA can help ensure compliance with all of PREA's requirements and get you through FDA as quickly and smoothly as possible. To learn more about our services and how we can help you, contact us today.